Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was made to clarify the mechanisms of the antinephritic action of SA-446, an angiotensin I converting enzyme inhibitor, on crescentic-type anti-GBM nephritis in rats as compared to the actions of spironolactone (an antialdosterone agent), kallidinogenase (a kallikrein agent) and saralasin (an angiotensin II antagonist). SA-446 (25 mg/kg/day, p.o.) had a tendency to reduce the urinary protein excretion and plasma urea nitrogen content. In addition, this drug remarkably inhibited not only glomerular histopathological changes (i.e., crescent formation, the adhesion of capillary walls to Bowman's capsule and fibrinoid necrosis) but also the elevation of blood pressure. Spironolactone (25 mg/kg/day, p.o.) and kallidinogenase (25 KU/day, i.m.) also showed beneficial effects on glomerular histopathological changes and hypertension, although both drugs were not as effective as SA-446. However, saralasin (72 micrograms/day, s.c.) caused a marked aggravating action on this nephritis. This nephritic model showed a marked low activity of plasma renin all through the 40 day experimental period. In this model, the urinary aldosterone excretion was increased, in spite of the decrease in plasma renin activity. SA-446 and kallidinogenase significantly inhibited the decrease in plasma renin activity and the increase in urinary aldosterone excretion. Spironolactone inhibited only the increase in the aldosterone excretion. However, saralasin decreased the plasma renin activity under the control level and strongly increased the urinary aldosterone excretion (about 1.8 times the control level on the 20th day). These results suggest that the antinephritic effect of SA-446 may be related to the antihypertensive action and the increase in renal blood flow through activation of the kallikrein-kinin and prostaglandins systems.
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PMID:Studies on mechanisms of antinephritic action of SA-446 an angiotensin I converting enzyme inhibitor (1). A comparison with actions of spironolactone, kallidinogenase and saralasin. 302 37

An isolated perfused kidney system (IPK) was used to study the direct intrarenal hemodynamic effects of binding of anti-glomerular-basement membrane (anti-GBM) antibody in the absence of all other circulating humoral and cellular inflammatory mediators. Control IPK's (perfused with Krebs-Henseleit buffered 5% albumin solution containing non-immune globulin) had a renal vascular resistance (RVR) mean +/- SEM 3.10 +/- 0.47 mm Hg/ml/min and a GFR mean +/- SEM 0.63 +/- 0.8 ml/min/g. Anti-GBM antibody administration raised RVR (4.83 +/- 0.52 mm Hg/ml/min, P less than 0.01) and lowered GFR (0.34 +/- 0.04 ml/min/g, P less than 0.01). Perfusate renin activity was higher after antibody administration (684 +/- 87 ng AI/ml/hr compared with control 308 +/- 42 ngAI/ml/hr, P less than 0.01). Treatment with Sar1Ala8All (3 X 10(-6) M) or captopril (10 mg/ml) attenuated antibody-induced vasoconstriction (RVR mm Hg/ml/min, Sara1Ala8All = 3.78 +/- 0.13 captopril = 3.26 +/- 0.12, both P less than 0.05 compared with anti-GBM alone). Both inhibitors of the renin-angiotensin system (RAS) also aggrevated the decline in GFR seen after antibody administration (GFR ml/min/g, Sara1Ala8All = 0.24 +/- 0.05, Captopril = 0.18 +/- 0.03, both P less than 0.05 compared with anti-GBM alone). These IPK studies demonstrate that anti-GBM antibody itself may directly induce intrarenal hemodynamic alterations in the absence of complement activation, neutrophil infiltration, neural influences or circulating vasoactive substances. The results from perfusate renin sampling and blockade of the RAS provide evidence that anti-GBM antibody deposition activates the intrarenal RAS and thereby induces significant hemodynamic alterations.
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PMID:Intrarenal hemodynamic alterations induced by anti-GBM antibody. 355 Feb 17

The small GTPase RhoA is activated by the angiotensin II (AngII) type 1 receptor (AT1R), which is part of the local renin-angiotensin system that is involved in podocyte injury preceding glomerular crescent formation. We demonstrated previously that inhibition of AT1R protects against crescentic glomerular injury in Fc receptor-deficient mice (gamma -/-) with anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM GN). Here, we hypothesized that the RhoA kinase inhibitor, fasudil, attenuates AT1R-dependent crescentic GN. We examined anti-GBM GN in gamma -/- mice with or without fasudil treatment, and further investigated the underlying mechanisms in cultured differentiated podocytes and leukocytes. Fasudil markedly attenuated crescentic GN with a significant decrease in proteinuria and hematuria, infiltration of T cells and monocytes/macrophages as well as their local proliferation, and preservation of podocyte-specific proteins, including WT-1 and nephrin, in glomeruli. In vitro studies showed that AngII induced the down-regulation of both nephrin and WT-1 expression in podocytes, which was reversed by fasudil in a dose-dependent manner. Additionally, fasudil blocked the AngII-induced migration of both macrophages and T cells. Furthermore, we also examined lipopolysaccharide-induced nephrotic syndrome in severe combined immunodeficiency disease mice and found that fasudil failed to block the development of proteinuria because of a B7-1-dependent podocyte injury. In conclusion, fasudil treatment prevents crescent formation and disease progression in anti-GBM GN by preventing AngII-induced podocyte injury and leukocyte migration.
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PMID:Amelioration of crescentic glomerulonephritis by RhoA kinase inhibitor, Fasudil, through podocyte protection and prevention of leukocyte migration. 1824 10

The various types of glomerulonephritis, including many forms of vasculitis, are responsible for about 15% of cases of end-stage renal disease (ESRD). Arterial hypertension represents a frequent finding in patients suffering from glomerulonephritis or vasculitis and hypertension also serves as an indicator for these severe types of diseases. In addition, there are symptoms and signs like hematuria, proteinuria and renal failure. Especially, rapidly progressive glomerulonephritis (RPGN) constitutes a medical emergency and must not be missed by treating physicians. This disease can either occur limited to the kidneys or in the context of a systemic inflammatory disorder, like a vasculitis. If left untreated, RPGN can lead to a necrotizing destruction of glomeruli causing irreversible kidney damage within several months or even weeks. With respect to the immunologically caused vasculitis, there are - depending upon the severity and type of organ involved - many clinical warning signs to be recognized, such as arterial hypertension, hemoptysis, arthalgias, muscle pain, palpable purpura, hematuria, proteinuria and renal failure. In addition, constitutional signs, such as fever and loss of body weight may occur concurrently. Investigations of glomerulonephritis or vasculitis must contain a careful and complete examination of family history and medications used by the respective patient. Thereafter, a thorough clinical examination must follow, including skin, joints and measurement of arterial blood pressure. In addition, a spectrum of laboratory analyses is required in blood, such as full blood screen, erythrocyte sedimentation rate, CRP, creatinine, urea and glucose, and in urine, including urinalysis looking for hematuria, red cell casts and proteinuria. Importantly, proteinuria needs to be quantified by the utilization of a random urine sample. Proteinuria > 3g/d is diagnostic for a glomerular damage. These basic tests are usually followed by more specialized analyses, such as a screening for infections, including search for HIV, hepatitis B or C and various bacteria, and for systemic inflammatory diseases, including tests for antibodies, such as ANA, anti-dsDNA, ANCA, anti-GBM and anti-CCP. In cases of membranous nephropathy, antibodies against phospholipase-A2-receptor need to be looked for. Depending upon the given clinical circumstances and the type of disease, a reasonable tumor screening must be performed, especially in cases of membranous and minimal-change nephropathy. Finally, radiological examinations will complete the initial work-up. In most cases, at least an ultrasound of the kidney is mandatory. Thereafter, in most cases a renal biopsy is required to establish a firm diagnosis to define all treatment options and their chance of success. The elimination of a specific cause for a given glomerulonephritis or vasculitis, such as an infection, a malignancy or a drug-related side-effect, remains the key principle in the management of these diseases. ACE-inhibitors, angiotensin receptor-blockers, aldosteron antagonists and renin-inhibitors remain the mainstay in the therapy of arterial hypertension with proteinuria. Only in cases of persistently high proteinuria, ACE-inhibitors and angiotensin receptor blockers can be prescribed in combination. Certain types of glomerulonephritis and essentially all forms of vasculitis require some form of more specific anti-inflammatory therapy. Respective immunosuppressive drug regimens contain traditionally medications, such as glucocorticoids (e. g. prednisone), cyclosporine A, mycophenolate mofetil, cyclophosphamide, and azathioprine. With respect to more severe forms of glomerulonephritis and vasculitis, the antibody rituximab represents a new and less toxic alternative to cyclophosphamide. Finally, in certain special cases, like Goodpasture's syndrome or severe ANCA-positive vasculitis, a plasma exchange will be useful and even required.
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PMID:[Glomerulonephritis and vasculitis as causes of arterial hypertension]. 2254 60